Synthesis and Study of the Hepatoprotective Activity of New Uracil Derivatives

Objective: Pyrimidine base derivatives having a wide spectrum of pharmacological activity along with low toxicity are used as active ingredients of many drugs. Specifically, a large number of uracil series compounds have antitumor, anti-inflammatory, antiviral, and immunomodulatory effects, which makes relevant the synthesis of new biologically active derivatives of the pyrimidine series. It is known that the mechanism of hepatotoxicity of chemical compounds is largely associated with the activation of lipid peroxidation, therefore, the objects of the study were uracil derivatives containing a proton-donating group in position C5, which significantly increases the antioxidant properties of the compound. Methods: For the synthesis of uracil derivatives, modification of 5-hydroxy- and 5-amino-6-methyluracils, containing pre-protected C5 functional groups, with various alkyl substituents introduced at N¹,N³ positions was carried out. The method of preliminary etching of cells with the hepatotoxicant carbon tetrachloride and their treatment with the tested compounds was selected for the study of the hepatoprotective activity. Results and Discussion: The introduction of various alkyl substituents at the N¹,N³ positions of 5-hydroxy- and 5-amino-6-methyluracils was shown to increase the solubility of these compounds; the hepatoprotective activity of the synthesized compounds was revealed. Conclusions: New di- and monoalkyl derivatives of 5-hydroxy- and 5-amino-6-methyluracils were obtained, and their hepatoprotective activity was tested in vitro. According to the test results, five of the 20 new compounds synthesized promote cell survival when pretreated with carbon tetrachloride.